Tuesday, May 31, 2011

The following twelve proposals were recommended for full funding by the Congressionally Directed Medical Research Program (CDMRP) integration panel in December. They were publicly announced at last week’s Research Advisory Committee (RAC-GWVI) meetings in Washington, DC.

While these twelve represent among the best of those proposed, our panel had a very challenging time selecting from among the many excellent proposals submitted. Simply put, the panel could have funded quite a few additional and important treatment-focused studies had there been more funding available.

Future funding for the program will be especially important given that three “consortium” proposals were funded – essentially infrastructure building to enhance the collective efforts of a virtual “Who’s Who” of clinical and scientific researchers actively engaged in unlocking the keys to understanding and treating Gulf War Illness.

“We are extremely disappointed that the editor of Science has published an “editorial expression of concern”, regarding the Lombardi et al. study. The authors of the Lombardi study believe that it is premature to conclude that the negative studies are accurate or change the conclusions of the original studies and we fully agree,” said Annette Whittemore, President of the Whittemore Peterson Institute. “Much of the work on this new retrovirus has yet to be performed, and we look forward to new studies which will support the results and findings described by these accomplished scientists. There has been no attempt to fully replicate this study to date. All of the negative studies have failed to use the methods, materials or processes used in the original study and many have been poorly designed. WPI researchers will continue to perform the critical research needed to help the patients who suffer from neuro-immune disease.” In addition, the WPI will continue to offer other scientific researchers the materials and methods necessary to perform a full and accurate replication study in the future.

About The Whittemore Peterson InstituteThe Whittemore Peterson Institute is the nation’s first comprehensive translational research facility dedicated to neuro-immune disease research, treatment, education and outreach.

The latest Science papers are not the final word on XMRV. The US National Institutes of Health is sponsoring two studies in which several different labs are testing blinded samples from CFS patients and healthy controls.

One, known as the Blood Working Group, should have the results of tests for XMRV in about 30 people with CFS by this summer. While a second, larger study, coordinated by Columbia University virologist Ian Lipkin, should be complete by year’s end. Read more>>

In summary, human retroviruses are not known to infect individuals according totheir sex or age therefore there can be no excuse as to why it would be acceptable tostudy the viruses in cancer but not in those with infectious neuro-immune diseases.They create lifelong infection in their hosts by integrating into the genome of theirvictims. Thirty years of murine gammaretroviral research provide compelling evidencethat these viruses cause immune deficiencies, neurological disease and cancer inmammals and are therefore possible contributors to human neuro-immune diseasessuch as CFS. However, good scientific work is difficult and takes time. These ongoingstudies deserve to receive a fair and impartial evaluation in the peer-review process. The critical question which remains is not simply whether gammaretroviruses play a role in CFS or cancer but in how many other human diseases? Therefore, we feel this is an extremely premature action which is not in the best interest of the scientific community or human health and again we respectfully request that you allow the scientific process to run its course unhindered by bias.

As the corresponding author of the Lombardi et al. study I want to express mydeepest concern about the proposed issuance of your editorial expression of concernregarding our XMRV findings and its association with chronic fatigue syndrome. This is especially so in light of the gross disregard for the integrity of the scientific process by the apparent willful breach of your embargo by one of the authors or their collaborators.

This has resulted in the apparent public knowledge of the contents of your request that we retract our seminal paper. I would respectfully ask that you focus on the following key facts and reconsider your position. We share your deep concern over the number of negative non-replication studies in this new area of research. However, the publication of your editorial expression of concern over the validity of Lombardi et al. findings are premature and would have a disastrous impact on the future of this field of science.Please do not proceed down a path that could be detrimental to the scientific exploration of human retroviruses in infectious disease, cancer, and, therefore, the future health of millions around the world.Read more>>

The novel human retrovirus XMRV has been associated with prostate cancer and chronic fatigue syndrome. The nucleotide sequence of XMRV isolated from humans indicates that the virus is nearly identical with XMRV produced from a human prostate tumor cell line called 22Rv1. This cell line was derived by passage of human prostate tumor tissue in nude mice. Sequence analyses reveal that the genomes of these mouse strains contain two different proviral DNAs related to XMRV. These viral genomes recombined to produce XMRV that has been isolated from humans.

XMRV was originally isolated from a human prostate cancer in 2006, and subsequently associated with ME/CFS. The human cell line 22Rv1, which was established from a human prostate tumor (CWR22), produces infectious XMRV. An important question is whether XMRV was present in the original prostate tumor, or was obtained by passage through nude mice. To answer this question, DNA from various passages of the prostate tumor in nude mice (called xenografts), and the mouse strains used to passage the tumor, were analyzed for the presence of XMRV proviral DNA.

Early-passage xenografts did not contain XMRV, but mouse cells found in them did contain two related proviruses called PreXMRV-1 and PreXMRV-2. The 3’-3211 nucleotides of PreXMRV-1, and both LTRs, are identical to XMRV save for two nucleotide differences. The genomic 5’-half of XMRV and PreXMRV-1 differs by 9-10%. PreXMRV-1 is defective for replication due to mutations in genes encoding the gag and pol proteins. PreXMRV-2 does not contain obvious mutations that would prevent the production of infectious viruses. The gag-pro-pol and a part of the env region of this viral genome is identical to that of XMRV save for two base differences; the LTRs and the remainder of the genome differ by 6-12% from XMRV.

Comparison of the sequences of PreXMRV-1 and PreXMRV-2 indicates that recombination between the two viral genomes led to the formation of XMRV. When the sequences of PreXMRV-1 and −2 are used to construct the recombinant XMRV, the resulting virus differs by only 4 nucleotides from the consensus XMRV sequence derived from all human isolates reported to date.

The nude mice used for passage of the original prostate tumor were likely the NU/NU and Hsd strains. Neither mouse strain contains XMRV proviral DNA, but both contain PreXMRV-1 and PreXMRV-2 proviral DNA.

These data demonstrate that XMRV was not present in the original CWR22 prostate tumor, but arose by recombination of PreXMRV-1 and PreXMRV-2 between 1993-1996. When the original prostate tumor was implanted into nude mice, some of the mice harbored both pre-XMRV-1 and −2 endogenous proviruses, which recombined to form XMRV. The authors believe that XMRV originating from the CRWR22 xenografts, the22Rv1 cell line, or other related cell lines has contaminated all human samples positive for the virus. In addition, they suggest that PCR assays for XMRV may actually detect PreXMRV-1 and −2 or other endogenous viral DNA from contaminating mouse DNA.

Another possibility to explain the origin of XMRV is that it arose in mice and can infect humans. If this is true, then XMRV would have to be present in the nude mice used to passage the CWR22 human prostate tumor. No evidence for an XMRV provirus was found in 12 different nude mouse strains, including two used to passage the CWR22 tumor. Furthermore, a screen of 89 inbred and wild mice failed to reveal the presence of proviral XMRV DNA. Hence the authors conclude:

…that XMRV arose from a recombination event between two endogenous MLVs that took place around 1993-1996 in a nude mouse carrying the CWR22 PC xenograft, and that all of the XMRV isolates reported to date are descended from this one event.

It is possible that XMRV produced during passage of CWR22 in nude mice subsequently infected humans. Because XMRV arose between 1993-1996, this scenario could not explain cases of prostate cancer and chronic fatigue syndrome that arose prior to that date.

How can these findings be reconciled with the published evidence that sera of ME/CFS patients from the 1980s contain antibodies to XMRV? Those antibodies were not shown to be directed specifically against XMRV, and therefore cannot be used to prove that XMRV circulated in humans prior to 1993-96. Furthermore, in the absence of clear isolation of an infectious virus, antibody tests alone have proven highly unreliable for identification of new viruses.

Where do these findings leave the hypothesis that XMRV is the etiologic agent of prostate cancer and ME/CFS? All published sequences of human XMRV isolates are clearly derived by recombination of PreXMRV-1 and −2. The finding of human XMRV isolates that are not derived from PreXMRV-1 and −2 would leave a role for XMRV in human disease. As of this writing, no such XMRV isolates have been reported in the scientific literature.

Update: A second paper has also been published in Science Express today entitled “No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected”. Editors of the journal Science have asked the authors to retract their 2009 paper linking XMRV infection with chronic fatigue syndrome. The authors have refused.

The use of a mouse-derived vaccine as asingle source of XMRV infection could explain thelow genetic variation of XMRV sequences isolatedfrom different individuals in different geographiclocations. Read more>>

These findings indicate that even though it is likely thatmany positive cases may have to be dismissed asrepresenting contamination with mouse DNA,genuine human infections with XMRV seem toexist at a relatively low prevalence.

In retrospect, the method used in most studiesfor detection of XMRV, almost exclusivelynested PCR amplification, has been a rather unluckychoice. In clinical virology, a putative virusinfection is usually probed with a serologicalassay, although real time PCR assays are currentlyin use for infections in which a high copy numberof viral nucleic acid (RNA or DNA) is knownto correlate with disease. A simple detection PCRis rarely the first method of choice for several reasons,including the danger of getting false positivesdue to contamination. Serological assays forXMRV are currently being developed, and will bemuch needed to distinguish genuine infected patientsfrom contamination cases.

Serology will be more informative than running a control PCRfor mouse DNA as contamination by XMRV particles(e.g. from protein preparations or contaminatedcell cultures) will not show mouse DNA,other than the viral genome. Read more>>

These findings indicate that even though it is likely thatmany positive cases may have to be dismissed asrepresenting contamination with mouse DNA,genuine human infections with XMRV seem toexist at a relatively low prevalence.In retrospect, the method used in most studiesfor detection of XMRV, almost exclusivelynested PCR amplification, has been a rather unluckychoice. In clinical virology, a putative virusinfection is usually probed with a serologicalassay, although real time PCR assays are currentlyin use for infections in which a high copy numberof viral nucleic acid (RNA or DNA) is knownto correlate with disease. A simple detection PCRis rarely the first method of choice for several reasons,including the danger of getting false positivesdue to contamination. Serological assays forXMRV are currently being developed, and will bemuch needed to distinguish genuine infected patientsfrom contamination cases.

Serology will be more informative than running a control PCRfor mouse DNA as contamination by XMRV particles(e.g. from protein preparations or contaminatedcell cultures) will not show mouse DNA,other than the viral genome. Read more>>

These findings indicate that even though it is likely thatmany positive cases may have to be dismissed asrepresenting contamination with mouse DNA,genuine human infections with XMRV seem toexist at a relatively low prevalence.In retrospect, the method used in most studiesfor detection of XMRV, almost exclusivelynested PCR amplification, has been a rather unluckychoice. In clinical virology, a putative virusinfection is usually probed with a serologicalassay, although real time PCR assays are currentlyin use for infections in which a high copy numberof viral nucleic acid (RNA or DNA) is knownto correlate with disease. A simple detection PCRis rarely the first method of choice for several reasons,including the danger of getting false positivesdue to contamination. Serological assays forXMRV are currently being developed, and will bemuch needed to distinguish genuine infected patientsfrom contamination cases.

Serology will be more informative than running a control PCRfor mouse DNA as contamination by XMRV particles(e.g. from protein preparations or contaminatedcell cultures) will not show mouse DNA,other than the viral genome. Read more>>

if anyone is wondering why an assay that can find a low copy number of the VP-62 clone cant find wt virus the answer is relatively simple

The chemophysical properties of the DNA are different

high levels of oxidative stress caused by hgrv infections and commonly found in studies investigating patients with ME cause oxidative modification of nucleotide bases. The most common is the addition of a hydroxyl functional group or deamination. This (for reasons involving sterochemistry and something called twisting) means that the stacking energy and hydrogen bonding which hold complimentary nucleotide bases together are dramatically reduced. This can be compensated for by using increased levels of magnesium and lowering annealing temperatures.Another strategy is to use an RNA template to begin with. mlv viruses cant replicate in resting cells so xmrv will exist in such cells as preintegrative complexes and integrated highly methylated proviruses. ROS oxidation induces a pattern of base substitution or inversion in the provirus affecting primer annealing.The presence of certain oxidised bases or even abasic sequences can stop taq polymerase "in its tracks" leading to an absence of product.Unless PCR reagent concentrations and cycling conditions are adjusted accordingly the virus will escape detection. silverman was able to adjust his assays to find gag sequences which were already present and was fortunate enough to isolate XMRV from RNA hence largely avoiding these issues

The effect of activating PMBcs would be to allow the integration of "fresh" proviruses as the preintegrative complexes are nowhere near as prone to oxidative damage.This would also allow the creation of viral RNA

I will post the detailed version but I wanted to post this to demonstrate what a BS decision the Science editors are making

"Science" has abandoned Science. I hope that its subscribers take note

Professor Malcolm Hooper’s Detailed Response to Professor Peter White’s letter to Dr Richard Horton about his complaint re: the PACE Trial articles published in The Lancet

28th May 2011

(Note that the complaint submitted by Professor Hooper to which Professor White responded can be accessed at http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.htm ).

Professor Hooper believes that there are two related issues: (A) the inaccuracies in the undated letter sent by Professor Peter White on behalf of the co-authors of the PACE Trial article to Dr Richard Horton, Editor-in-Chief of The Lancet, refuting his complaint and (B) what Professor Hooper continues to believe are failures by The Lancet to fulfil its ethical duties with regard to the preparation and publication of the PACE Trial articles. Both are addressed in this document.

As Professor White’s letter is written in the third person, Professor Hooper has done likewise.

Part A: Reply to Professor Peter White’s response to the complaint submitted to The Lancet

Professor White’s letter, which can be read here, that was forwarded to Professor Hooper by Zoe Mullan, Senior Editor at The Lancet, appears to contain factual inaccuracies and errors; these are here addressed in order of presentation in Professor White’s letter.

In the interests of transparency, Professor White’s letter itself, together with evidence supporting an important aspect of the complaint to The Lancet, will be placed in the public domain together with this response. Read more>>

As a science reporter and blogger, what I find most perplexing about the Science editors asking Dr. Mikovits to withdraw her study is that the jury is clearly still out. While some laboratories haven’t found XMRV in CFS patients, others have. The ones that haven’t found XMRV failed to replicate the methods and patient cohort of the original Science study, making their findings questionable. The laboratories that have found the retrovirus include a study by National Institutes of Health Lasker Award winner Dr. Harvey Alter and the FDA’s Dr. Shyh-Ching Lo. Their study found variants of XMRV in 86 percent of patients and 7 percent of apparently healthy controls. All the controls were blood donors, signaling a contamination of the blood supply.

In addition, the original Science study was coauthored by the Cleveland Clinic and the National Cancer Institute, both of which also found the retrovirus in CFS patients. Moreover, other laboratories have found the retrovirus in CFS patients but have not yet published their findings. And, finally, respected laboratories have found the retrovirus in prostate cancer patients as well, making the contamination theory less than likely.

Given that others have replicated Mikovits’ findings, given the high stakes in a population that has no treatment after 30 years of government neglect, given that many CFS patients have died from the disease and many others experience a living death, I find it problematic that Science has asked Dr. Mikovits to withdraw the paper.

Some see this move as the first step to shutting down current NIH-sponsored XMRV CFS studies, as the government did 20 years ago, when the first evidence of a retrovirus in CFS patients surfaced at the Wistar Institute at the University of Pennsylvania. Back then, the Centers for Disease Control refused to replicate the methods of Wistar’s Dr. Elaine DeFreitas. When the CDC couldn’t replicate her findings, the research died. Twenty years later, it’s deja vu all over again.

Science seems to be hell bent on consensus, but as Harvard-educated physician and medical thriller writer Dr. Michael Crichton once pronounced: “Let’s be clear: The work of science has nothing whatever to do with consensus. Consensus is the business of politics. Science, on the contrary, requires only one investigator who happens to be right....”

Whether Dr. Mikovits is right is anyone’s guess. But asking her to withdraw her paper before the truth is known is the antithesis of science.

Editors of the journal Science have asked the co-authors of a 2009 paper that linked chronic fatigue syndrome to a retrovirus called XMRV to voluntarily retract the paper.

But in written response Friday, study co-author Judy A. Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease said "it is premature to retract our paper." The letter was reviewed by the The Wall Street Journal.

The study raised patients' hopes that if a virus was linked to chronic fatigue syndrome, a treatment might be found. Public-health officials were alarmed by the possibility that supposedly healthy people might unknowingly be infected with a contagious retrovirus. The federal government began an ongoing effort to evaluate whether the nation's blood supply was safe, work that continues.

In the May 26 letter to Dr. Mikovits and her co-authors, also reviewed by the Journal, Science editor-in-chief Bruce Alberts and executive editor Monica Bradford cited concerns about the validity of the findings, saying other scientists hadn't been able to replicate them, among other reasons.

Dr. Mikovits, who confirmed the letters, said she hadn't received a response in return. Dr. Alberts and Ms. Bradford at Science couldn't be reached for comment.

After the 2009 study, other published studies showed that some anti-retrovirals approved for use in HIV might also be effective against XMRV. Some doctors began prescribing anti-retrovirals for chronic fatigue syndrome patients.

The concern about the blood supply led blood banks to bar patients with chronic fatigue syndrome from donating. An advisory committee to the federal Food and Drug Administration recommended last year that the FDA bar people with chronic fatigue syndrome from donating. The FDA hasn't weighed in on the recommendation.

The Centers for Disease Control and Prevention, among other groups, published studies reporting they didn't find XMRV in chronic fatigue syndrome patients. Other papers found that substances used as part of the process to detect XMRV might be contaminated, raising the possibility that this may explain the positive findings in the 2009 Science paper.

In the letter to the study authors, Dr. Alberts and Ms. Bradford suggested the paper be withdrawn "in light of the growing number of research papers from independent investigators who have either failed to replicate your original finding that XMRV is associated with chronic fatigue syndrome and/or who have provided evidence that laboratory reagents are widely contaminated with the virus."

The letter added that two additional papers that "cast further doubt'' on the 2009 paper's findings will be published on June 2 in Science, and that Science will be publishing what it called an editorial expression of concern about the 2009 paper. "At this juncture, Science feels that it would be in the best interest of the scientific community'' for the co-authors to retract the paper, the letter stated.

An editorial expression of concern, while falling short of the journal outright retracting a paper itself, raises a red flag to the scientific community that serious doubts exist about a paper's findings and can make it harder for researchers to obtain funding or publish papers, says R. Grant Steen, a medical communications consultant. He has published papers analyzing 742 English language research papers that were retracted from the PubMed database from 2000-2010.

The 2009 study in question, led by investigators at Whittemore Peterson in Reno, Nev., and including researchers from the National Cancer Institute and the Cleveland Clinic, generated enormous attention among scientists and patients. The researchers reported they found the retrovirus XMRV in a majority of 101 patients with chronic fatigue syndrome, a debilitating condition that involves cognitive dysfunction and severe pain. The authors also found the virus in nearly 4% of 218 healthy people used as controls in the study.

Dr. Mikovits said it was still too early to know the reasons for the differing results in different labs, and that the Institute was looking forward to participating in a major study under way by the NIH and led by Columbia University scientist Ian Lipkin to help clarify the matter.

Monday, May 30, 2011

DZ: When a new study, like Peterson's, comes out, look carefully - did they prove their assay can detect viral nucleic acid that has been integrated into DNA or otherwise subjected to the unique environment of a human body? In other words, has their assay been clinically validated? If not, and they found little or nothing, one really cannot be sure that their assay works on human samples at all.

HGRVs cannot replicate in resting cells. They integrate into host DNA. XMRV (one variant of HGRV) integrates preferentially into CpG islands which have a huge c-g content and hence are an example of the complex secondary structures discussed below. HGRVs also exist in amethylated state and as such are very prone to oxidative stress. This either leads to mispriming, mismatches or reduces the binding strength between complimentary bases. Therefore, PCR faces completely different challenges in this environment than it does when being used to locate a non integrated naked clone in a spiked sample. Read more>>

Sunday, May 29, 2011

When it comes to patients, people like me are trained to respect them all. As for the diseases patients carry, that's a very different story. This week on White Coat, Black Art: diseases that get little respect inside the hospital's sliding doors. I speak with a Vancouver woman whose medical condition has generated everything from skepticism to outright disbelief from many of the doctors who've treated her. And, a medical historian explains why some diseases get a lot of respect while others don't, and whether marketing can change that.

Tune in Saturday at 11 am (11:30 am NT) and again on Monday at 11:30 am (3:30 pm NT) on CBC Radio One. Or, click below to listen to the show right now, or download the podcast.

In medical circles, there are diseases that command respect among physicians. Multiple sclerosis, rheumatoid arthritis and strokes are three such examples. These and many others have two things in common. First, they are serious conditions in that they are either life threatening or cause serious disability. Second, they can be confirmed objectively through blood work, CT scans, MRIs, and other forms of testing.

Cancer may well top the list. Even so, some forms of cancer get more respect than others. As reported by CBC News, in terms of fundraising and research dollars, we tend to respect breast, prostate, childhood cancers and leukemias far more than lung, colorectal and stomach cancers. That's surprising since it's the latter three types of cancer that are among the most common and most deadly.

Then again, there's a category of medical conditions you'd swear people like me are trained or acculturated to disrespect if not view with outright contempt - no matter how much that makes you suffer.

Comedian Rodney Dangerfield made a successful stand-up career out of getting no respect. It's fair to say the Rodney Dangerfield of diseases is one called Fibromyalgia (FM). It's a condition that causes pain, stiffness, fatigue, poor sleep, plus trouble thinking and concentrating. According to a recent review article, roughly five percent of the population has FM, with the highest prevalence occurring in middle-aged women.

Researchers are zeroing in on the cause of FM. It is now seen as a biological neurosensory disorder characterized in part by abnormal processing of pain signals in the central nervous system. Along with a new understanding of the biological basis of FM have come new drug treatments to relieve the symptoms. Not only that, in 1990, the American College of Rheumatology published guidelines on how to make the diagnosis.

Still, it's hard to find a disease with less respect among people like me. None of this is news to Susan MacLean, a patient with FM and President of Myalgic Encephalomyelitis and Fibromyalgia Society of BC (MEFM) who began by battling the disease and ended up battling many of the doctors who treated her.

"I've had a number of very negative reactions from doctors," MacLean told WCBA. "I'd like to describe my experience when I actually received the diagnosis of FM.

"I was seeing a doctor for a number of months before a referral to a specialist was actually made. The reaction of the rheumatologist was that this was an illness of high-strung, uptight middle age women, that I should buy new shoes to alleviate the excruciating pain in my feet and legs.

"They did a very cursory physical examination, handed me a brochure, told me not to seek out any support for the illness from any of the local support groups in town, because that was simply a bunch of people sitting around, holding hands feeling sorry for themselves.

"I was patted on the back, escorted out of the office, and was told that they hoped they never saw me again," recalls MacLean.

Other modern day illnesses that have been disrespected by physicians include chronic fatigue syndrome and - at least until recently - concussion. Read more>>

Many with a medical illness seek comrades on similar journeys. Psychotherapy and support groups, internet chat rooms and blogs are all ways of connecting with one's illness companions. Says one patient of his MS psychotherapy group: "they're my brethren". Despite the fact that his group is not heterogeneous (the degree of impairment ranges dramatically among members) he discovers they have a common ground — and a common enemy — uniting them. The group provides health-enhancing strength and a safe space where members can speak their fears aloud: progression, burdening others, challenging relationships, role shifts, financial and career anxieties. They bolster each other with coping tools. When one member has a relapse, they rally around their comrade and find comfort in each other.

Of course, venues such as therapy and support groups are not for everyone. Some medically ill people prefer to "be alone", and choosing to be alone is distinct from a sense of disconnection and isolation. Being alone in medical illness can provide solace, space for reflection, contemplation and self-assessment as well as a feeling of control and direction. The person who is alone — but not lonely — may find self-connection through religion, spirituality, or artistic immersion, for example. No question, these can be profoundly valuable supports. Yet, they are not necessarily antidotes to the existential loneliness that so many medically ill persons experience.

Often the remedy is finding a community where the unspoken feelings around illness not only can be spoken but are routinely given voice. My patients tell me that encountering and engaging with others who share their illness lifts the pallor of isolation, the barrier that separates the healthy from the ill. "Our lives are not tragic," says Elisa of the cancer-sharing couple. Going through any medical illness "together", with others on a similar journey, is far better than going it alone.Read more>>

Department of Anesthesiology, University of Utah, Salt Lake City, UT The Brain Institute, University of Utah, Salt Lake City, UT Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT Department of Exercise and Sprt Science, University of Utah, Salt Lake City, UT.

AbstractLight AR, Bateman L, Jo D, Hughen RW, VanHaitsma TA, White AT, Light KC (University of Utah Dept. Anesthesiology, Dept. Neurobiology and Anatomy, Dept. Exercise and Sport Science) Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia Syndrome. Objectives: To determine mRNA expression differences in genes involved in signaling and modulating sensory fatigue, and muscle pain in patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia Syndrome (FM) at baseline, and following moderate exercise. Design: Forty eight Patients with CFS-only, or CFS with comorbid FM, 18 Patients with FM that did not meet criteria for CFS, and 49 healthy Controls underwent moderate exercise (25 minutes at 70% maximum age predicted heart-rate). Visual-analogue measures of fatigue and pain were taken before, during, and after exercise. Blood samples were taken before, and 0.5, 8, 24, and 48 hours after exercise. Leukocytes were immediately isolated from blood, number coded for blind processing and analyses, and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic, and immune functions was compared between groups at baseline, and following exercise. Changes in amounts of mRNA were correlated with behavioral measures, and functional clinical assessments. Results: No gene expression changes occurred following exercise in Controls. In 71% of CFS patients, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 hours. These post-exercise increases correlated with behavioral measures of fatigue and pain. In contrast, for the other 29% of CFS patients, adrenergic α-2A receptor's transcription was decreased at all time points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM only patients showed no post-exercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than Controls. Conclusions: At least two subgroups of CFS patients can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the CFS patients with orthostatic intolerance, showed no post-exercise increases in any gene, and was defined by decreases in mRNA for α-2A. FM only patients can be identified by baseline increases in 3 genes. Post-exercise increases for 4 genes meet published criteria as an objective biomarker for CFS, and could be useful in guiding treatment selection for different subgroups.

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterized by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder.

Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients.

Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients.

Conclusions: Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.

For well over a decade the CAA has had an all too cozy collaborative relationship with the health department. Instead of being strong advocates for the needs of CFS patients the CAA has mostly taken actions to promote and bolster their own organizational economic interests. They have repeatedly betrayed the patient sector as they have acted as a puppet for the health department, most notably for the CDC. They were given many chances to correct their misguided wanderings yet they never did so. In turn the vast majority of the CFS patient and medical sectors came to the conclusion that they could no longer support the CAA. People do not forget betrayal, nor should they.

From time to time the CAA, PANDORA and a few other groups have deceptively called for unity. Sincere unity formed around common goals and actions is something we’d all wish to see. That’s not what their calls for unity are about though. Those organizations insist on being the directors on the stage of CFS advocacy and are adamant about doing things their way. While they speak of unity they will have little or nothing to do with others who have differing views. Collaboration to them means do it our way or don’t be included. Above all else they wish to quell being held accountable for their actions and behavior so they call for unity. It is a sham. People won’t forget this either.Read more>>

Imagine the following scenario: Your horse has a fever. He's recently been exposed to a horse that tested positive for the neurologic strain of equine herpesvirus-1 (EHV-1). You call your vet, who comes out and swabs the horse's nasal passages and draws a tube or two of blood. A few days later you get a call confirming that your horse is positive for EHV-1. What exactly happened from the time your horse's samples left your barn to when you got that call?

Equine herpesvirus-1 is highly contagious and can cause a variety of ailments in horses, including rhinopneumonitis (a respiratory disease usually found in young horses), abortion in broodmares, and myeloencephalopathy (the neurologic form). Clinical signs of EHV-1 myeloencephalopathy include fever, ataxia (incoordination), weakness or paralysis of the hind limbs, and incontinence. The virus is generally passed from horse to horse via aerosol transmission (when affected animals sneeze/cough) and contact with nasal secretions, but it isn't transmissible to humans.

An ongoing outbreak of the virus affecting several Western states and Canadian provinces (believed to have started at the National Cutting Horse Association's [NCHA] Western Regional Championship competition that ended May 8) has many horse owners asking questions about all aspects of EHV-1. Udeni Balasuriya, BVSc, PhD, professor of virology at the University of Kentucky's Gluck Equine Research Center, and Nicola Pusterla, DVM, PhD, Dipl. ACVIM, an associate professor in the Department of Medicine and Epidemiology at the University of California, Davis, shared some insight on what happens when a horse's sample arrives at the laboratory, and what test results mean.

Sample Collection and Submission

"The collection and submission of appropriate clinical samples for laboratory diagnosis is very important," Balasuriya said, noting the importance of the veterinarian procuring both nasal swabs and blood during any suspected EHV-1 outbreak.

Nasal swabs and blood samples provide a chance at finding the virus itself or viral DNA (indicating whether the horse is shedding the virus), while serum samples afford an opportunity to detect the horse's antibodies to the virus.Read more>>

AbstractAlthough XMRV dissemination in humans is a matter of debate, the prostate of select patients seem to harbor XMRV, which raises questions about its potential route of transmission. We established a model of infection in rhesus macaques inoculated with XMRV. In spite of the intravenous inoculation, all infected macaques exhibited readily detectable XMRV signal in the reproductive tract of all 4 males and 1 female during both acute and chronic infection stages. XMRV showed explosive growth in the acini of prostate during acute but not chronic infection. In seminal vesicles, epididymis and testes, XMRV protein production was detected throughout infection in interstitial or epithelial cells. In the female monkey, epithelial cells in the cervix and vagina were also positive for XMRV gag. The ready detection of XMRV in the reproductive tract of male and female macaques infected intravenously, suggests the potential for sexual transmission for XMRV.

The Countess of Mar, who through her Forward ME Group has provided a forum for all the major ME groups in the UK to speak with one voice, has been honoured for her outstanding achievement in the annual Dods Charity Champion Awards.

The Countess, pictured above after receiving her award in the Speakers Apartments at the House of Commons, was selected for the award by the awards scheme’s steering panel including Lord Archer of Sandwell, Charity Commission chair Dame Suzi Leather and former Labour minister Gisela Stuart MP, who edits parliament’s own ‘The House’ magazine.

In a message to the Forward ME Group, the Countess wrote:

I want to thank you all for the help and support I have received from you over the years. When I accepted it I did so on your behalf. The award is an attractive glass block which will look well on my mantelpiece.

The awards scheme is run on behalf of Dods Parliamentary Companion, which publishes briefing materials about people who work in the Palace of Westminster.

When the Countess founded the Forward ME Group in October 2008, she wrote:

Until the message you want to convey is heard loud and clear by legislators and government your objectives will never be achieved.

I have been in the House of Lords for very nearly 33 years. I have taken an active role in some successful campaigns and have watched the progress of other winners. What comes to my mind immediately is that they have always been supported by a united, informed and determined base of people who want to win.

One of my husband’s favourite sayings is “emotion clouds reason”. I fully appreciate that ME is a physically and mentally sapping illness and that a failure to achieve can lead to emotional stress, dissent and division in the ranks.

Over the years I have been made very aware of disagreements between the various representative organisations that, even when they are minor in fact, they are fairly major in effect. If I know about them then others who make the vital decisions at central and local level do so also. A difference of opinion – professional or lay, is a wonderful excuse for others to do nothing and doing nothing while going through the motions of construction is precisely what has been happening. I think of the CMO’s Report, the NICE Guidelines and all the advice emanating from the DoH and the DWP, for example.

Consider for a moment the reality of this illness and of those who suffer at the very bottom. This is where the nuts and bolts of this illness presents itself and where research needs to be directed. Natalie Bouton has done a great service for the rest of us and for the uninitiated by giving us the InvestinME sponsored book "Lost Voices" which documents the most seriously ill ME patients. Soon we will be able to see an astonishingly powerful video produced by Natalie and her son Josh. It packs a wallop and presents this illness at its ground zero moment. Read more>>

Tuesday, May 24, 2011

I'm speaking about the chronic fatigue syndrome/ME community and the way they view the autism parents. When I hear them speak this way I'm proud to belong to our group.

For those who are most severely affected by chronic fatigue syndrome/ME, often needing to lay in bed for most of the day with the curtains drawn, they refer to themselves as "the unburied dead."

My desire to assist this community is borne of simple human compassion, but also by the prospect that in their suffering they hold clues to what is going on with our own children.

Generation Rescue, Talk About Curing Autism, and the National Autism Association are all asking their members to support this effort to aid the Whittemore-Peterson Institute for Neuro-Immune Disorders in the Chase Community Giving Program.

Voting ends at midnight, EST, May 25, 2011. This is the last day to vote.

I know how strongly at least two of the autism groups feel because I set up the meeting with Dr. Judy Mikovits to go over her research into the XMRV retrovirus, chronic fatigue syndrome/ME, and yes, autism. The discussion lasted more than three and a half hours. Many questions were asked, but the feeling in the room was almost electric. We might be on the trail of an answer which explains what happened to our children, and also why so many mothers seem to have a myriad of health concerns. A retrovirus can explain many (if not all) observations reagrding autism, from co-infection by other pathogens, oxidative stress, mitochondrial problems, vaccines acting as a catalyst for the virus to replicate out of control, and mysterious ailments of the autism mothers.

Dr. Amy Yasko, whom I consider to be one of the brightest minds in autism, is excited about this research because it dovetails with many of her long-term observations and suspicions. The same can be said of Dr. Jeff Bradstreet.

It's time for the legions of the chronically ill, such as the autism, chronic fatigue syndrome/ME, Gulf War illness patients, and the hundreds of thousands of children with potentially life-threatenting allergies and their parents to band together in a single forum to raise our voices. Let this be a small step in that direction.

I know everybody is tired. I know there are so many battles to be fought, most concerning how to just get through the day with our sick children. My own daughter just came home a few days ago after spending nine days in the hospital with uncontrolled seizures. But for one last time I ask you to elevate your gaze and take a few moments to vote for the Whittemore-Peterson Institute for Neuro-Immune Disorders.

Here's how to do it:

1. From your Facebook page, go to Chase Community Giving:http://www.facebook.com/ChaseCommunityGiving

2. "Like" the Chase Community Giving by clicking on the "Like" button.

3. Now search for Whittemore Peterson Institute for Neuro-Immune Disease.

4. Cast your vote by clicking the "Vote Now!" button.

5. Search other organizations for whom you want to vote, up to 5 per Facebook account.Voting for round two is May 19 – May 25

About the conferenceThe aim of this biennial meeting is to promote discussion and share new findings between researchers and clinicians for the benefit of patients infected by human T-lymphotropic virus (HTLV). HTLV infects approximately 15-20 million individuals worldwide and causes a broad spectrum of diseases including neurodegeneration and leukemia. Due to the recent exciting discoveries in this field, a particular session will focus on endogenous retroviruses, foamy viruses and XMRV.

Saturday, May 21, 2011

Generation Rescue, Talk About Curing Autism, and the National Autism Association are teaming up to ask their members to vote for the Whittemore-Peterson Institutue for Neuro-Immune Diseases/University of Nevada-Reno in the Chase Community Giving Project, which ends on May 25.

In the first round, the Whittemore-Peterson Institute finished fifth in overall voting. This won them $25,000. The difference between fifth and first place was three thousand votes. In the second round the first place winner will receive $500,000.

Readers of this website know I've written many times about the work of the Whittemore-Peterson Institute and their work with XMRV retrovirus and autism. It's no secret I consider this to be one of the more promising areas of inquiry. Chronic fatigue syndrome/ME and autism share a number of immune system abnormalities.

However, the fact that Generation Rescue, Talk About Curing Autism, and the National Autism Association have agreed to help with this effort shows that this opinion is not held by me alone. I was also heartened to receive an e-mail the other day from Dr. Amy Yasko, letting me know she was also going to vote for the Whittemore-Peterson Institutue.

Let me tell you why I think that this vote is good for our community. We have long needed a world class facility dedicated to studying the problems of our children, staffed by scientists who are not afraid to ask challenging questions. I believe that describes the Whittemore-Peterson Institutue and the people who work in it. For those who believe this to be a worthwhile cause I strongly encourage people to get friends and relatives to vote as well. I have set a personal goal of gathering 100 votes from family and friends. I am currently at 10% of my goal.

After you vote for the Whittemore-Peterson Institute you will have four other votes to share among other charities you desire. Here is how you can vote.STEP-BY-STEP Instructions:

The Invest in ME Conference just ended a few hours ago. This conference brought new and exciting ressearch to ME that is soon to be published. Dr. David Bell discussed how the patients that he saw as children are now adults around 40 years old. Several have cancer, while others are still severly ill, but the majority are coping and say they are well but are actually still living with CFS. Dr. Demeirlier continues his important XMRV research, in Belgium and around the EU, finding many of the sickest patients positive for the retrovirus. Dr. Mikovits showed more "footprints" of XMRV infection from the patient's immune system data and described how XMRV seems to act more like HTLV than HIV. Dr. Bieger, a delightful iimunologist from Germany, is doing exciting work with XMRV and EBV. The rest will have to wait until the conference DVD is completed.

Discussions following the conference were very lively as those in the audience stated their frustration with the British medical/political establishment at not having adequate medical care in the UK. Howeveri, all in all, it was the best conference to date. I am overwhelmed with emotion over the expressions of thankfullness for all that the WPI is doing to bring awareness of this disease to the rest of the world. I wish we could all get together in one place to share stories and meet face to face. I realize how connected we've become, in our quest to find the answers to this devastating disease. I'll be flying home tomorrow while Judy travels to Ireland to give another presentation and more hope to those who suffer. Goodnight all! Annette Whittemore

The U.S. Food and Drug Administration today approved Edurant (rilpivirine) in combination with other antiretroviral drugs for the treatment of HIV-1 infection in adults who have never taken HIV therapy (treatment-naïve).

Edurant belongs to a class of HIV drugs called non-nucleoside reverse transcriptase inhibitor (NNRTI). The drug works by blocking HIV viral replication. Edurant is to be used as part of a highly active antiretroviral therapy (HAART) regimen that is designed to suppress the amount of HIV (viral load) in the blood. Edurant is a pill taken once a day with food.

“Patients may respond differently to various HIV drugs or experience varied side effects. FDA’s approval of Edurant provides an additional treatment option for patients who are starting HIV therapy,” said Edward Cox, M.D., M.P.H, director, Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

The safety and effectiveness of Edurant is based on 48-week data from two Phase 3 clinical trials with 1,368 adult subjects with HIV infection, and from a 96-week (with extension to 192 weeks) trial. Patients had not received prior HIV therapy and were selected to receive treatment with Edurant or efavirenz (another FDA-approved NNRTI for the treatment of HIV infection). Both drugs were given in combination with other antiretroviral drugs.

Edurant was as effective as efavirenz in lowering viral load. In the Edurant and efavirenz groups, 83 percent and 80 percent of subjects, respectively, had undetectable amounts of HIV in their blood after 48 weeks of treatment. Patients receiving Edurant who had a higher viral load at the start of therapy were more likely not to respond to the drug than were patients with a lower viral load at the start of therapy. In addition, persons who failed therapy with Edurant developed more drug resistance than patients who failed efavirenz.

The most commonly reported side effects in patients taking Edurant included depression, difficulty sleeping (insomnia), headache and rash. Fewer patients stopped taking the drug due to side effects as compared to patients taking efavirenz.

Edurant does not cure HIV infection. Patients must stay on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses.

There are now 33.2 million people living with human immunodeficiency type 1 (HIV-1) infection, and 2.6 million additional cases are diagnosed each year. The need for effective HIV-1 prevention has never been greater.

Clinical Pearls

• How quickly after exposure can HIV infection be detected?

Immediately after exposure and transmission, as HIV-1 is replicating in the mucosa, submucosa, and draining lymphoreticular tissues, the virus cannot be detected in plasma; this so-called eclipse phase generally lasts 7 to 21 days. The stages that define acute and early HIV-1 infection are characterized by the sequential appearance of viral markers and antibodies in the blood. More sensitive, fourth-generation tests, which detect both antigens and antibodies, shrink the virus-positive-antibody-negative window by about 5 days. Testing for viral RNA in plasma closes this gap by an additional 7 days.

• When are patients infected with HIV most contagious?

The per-person probability of transmitting HIV-1 is most closely correlated with the viral burden in blood; each time the viral burden in an HIV-1-infected person increases by a factor of 10, the risk of transmission is expected to increase by a factor of 2.5. The risk of contagion from patients with acute, early infection appears to be much higher than that from patients with established infection, at least in part because of the high viral load and the homogeneity of viral variants clearly capable of causing infection. Read more>>

In a written question, Ian Swales (Liberal Democrat MP for Redcar) asked the Secretary of State for Work and Pensions to state his policy on measures to ensure that people with ME who are unable to work are not required to undertake unsuitable work or work-related activity.

Employment Minister Chris Grayling replied on 19 May 2011:

We recognise that ME has a wide spectrum of symptoms and can be a severely debilitating condition. The effects of ME on an individual may contribute to someone meeting the entitlement conditions for benefits.

When someone’s health condition or disability, or the treatment they are receiving, makes it unreasonable to expect them to work we are committed to supporting them. The appropriate benefit in such cases is employment and support allowance (ESA). Entitlement to ESA is based on an individual’s functional ability rather than the condition itself. Anyone claiming ESA will undergo the work capability assessment. Those with the most severe functional limitations will be placed in the Support Group, for which the undertaking of work related activity is not a requirement.

People with limited capability for work will be placed in the Work-Related Activity Group. These individuals may be required to undertake work-related activity, detailed in their action plan, which must be reasonable in their circumstances. If they feel the requirement on them is unreasonable, they will be able to request the activity is reconsidered. Advisers will not be able to direct people on ESA to seek, apply for or do work, nor will they be directed to undertake medical treatment.

Thursday, May 19, 2011

By NKR:Every single vote counts! If you are on Facebook please take just a few seconds of your time to vote for the WPI - and then please encourage as many friends as you can to vote too. They need to beat several other organizations also vying for the same funds in order to win - if everyone with ME voted, they would win easily!

Remember mad cow disease? In the 1980s, cattle in the U.K. had begun contracting a fatal brain ailment triggered by an infectious protein called a prion. The pathogen could spread to humans who ate contaminated beef. Officials brought the bovine epidemic under control with major changes in agricultural practices.

Unfortunately, the same cannot be said for a cousin of the sickness, one that targets deer, elk and moose in the U.S. Called chronic wasting disease (CWD), or "mad deer" disease, the ailment poses an unusual challenge in that it has spread among wild populations, not among herded animals. Wild animals go where they may, so you cannot institute controls the way you can for livestock. So it comes as good news that a naturally occurring disinfectant exists within common lichens and might actually be able to stop prions in the wild.

What has made prions difficult to control is their infamous durability. Boil water for a few minutes, and all the bacteria and viruses will be gone. Not so for the prion: it will be just fine, ready to infect. How does it fare in a dry heat of 600 degrees C? No problem there, either. How about ionizing radiation? Bring it on.

The prion's stubbornness caused many unfortunate medical mishaps in the days before researchers knew what they were dealing with. In the 1970s, electrodes used to treat epilepsy spread a human prion disease from one patient to another even though the electrodes had undergone standard sterilization and sat for 18 months before reuse. In a later test on monkeys, electrodes maintained their infectivity even after three bouts of sterilization. In the late 1980s, the processing of cadaver tissue—specifically, a brain lining called the dura mater that is sometimes used as a patch in neurosurgery—failed to inactivate prions from infected donors, leading to the transmission of a fatal brain disease to healthy recipients. (I recount these and other incidents in my 2003 book on prions.)

And the prion's resistance to inactivation is a big reason why mad cow disease spread: to save money, the makers of cattle feed, which spread the illness, had eliminated the use of solvents and extended heating that probably would have disabled the prion. In decontaminating an area that once harbored infected farm animals (such as sheep), U.S. officials spray down hard surfaces with a caustic solution such as sodium hydroxide (better known as plumber's lye), turn over several centimeters of soil to bury any prions on the surface and deem the land off-limits for years. Such draconian measures are one reason why farmers dread the diagnosis, even with government reimbursement for the loss.

Of course, such techniques won't work in wild animals, which spread prions via their urine, feces and saliva. First identified in the late 1960s, chronic wasting disease has been detected in deer, elk and moose in 19 U.S. states and two Canadian provinces (although much of that spread resulted from the transfer of animals for game ranches). Although no human has contracted CWD from eating venison or other cervid meat, the lessons from the mad cow epidemic led game officials to conduct massive culls and establish stricter butchering guidelines to prevent contamination from brain and spinal tissue, where infectious prions collect.

So news that a natural answer exists for prions is welcome. In a paper published May 17 in PLoS One , Christopher Johnson of the U.S. Geological Survey of the National Wildlife Health Center in Madison, Wisc., and his team describe experiments with lichens, symbiotic collections of algae, fungus and bacteria that casual observers might mistake for moss. Three common species of lichens, the team has found, exude an enzyme that breaks down the prion.

The scientists achieved the results in a test tube, but they suspect that lichen power will work in the wild. "While great caution must be exercised in extrapolating in vitro studies to environmental conditions, our data suggest lichens could contribute to prion degradation on the landscape," they wrote, noting that inactivation might occur when prions come into direct contact with the lichens or with nearby soil. The team plans to test the hypothesis and even see if animals are protected from CWD if they eat the lichens.

Jose G. Montoya, MD, has treated more than 200 peoplewith chronic fatigue syndrome (CFS). The defining symptoms—disabling fatigue, brain fog, muscle and joint pain,impaired sleep, sore throat, and enlarged lymph nodes—indicate that a disease is clearly present. Whatever causesCFS, however, remains a mystery and a troubling concernfor patients who suffer from symptoms, which are ofteninconsistent with what laboratory tests and examinationscan actually find. Sadly, this profound dichotomy has led todisbelief among some physicians and members of the medicalcommunity as to whether patients are actually sick.For the past 6 years, Montoya, an associate professor in thedivision of infectious diseases, has postulated that CFS canbe linked to an infection from pathogens such as herpesviruses, Chlamydia pneumoniae, tick borne pathogens, orenteroviruses. “We have an increasing number of successstories where patients get better with long-term treatmentof the specific pathogen,” said Montoya.The problem, however, is that these different pathogensoften produce the same group of symptoms. “We have theequivalent to pneumonia as a disease in chronic fatiguesyndrome but haven’t found the infiltrate yet to objectivelysay this patient has CFS. We’re still working with the clinicaldefinition and to establish the relationship with thespecific pathogens.”Ongoing ResearchA $1.4 million grant from the pharmaceutical companythat manufactures the anti-viral drug Valcyte has enabledMontoya do a double-blind, placebo-controlled, randomizedtrial whose results are highly suggestive that patientsimprove because of the drug and not the placebo.Additional funds from a generous private donation fuelsthe search for pathogens in the blood of CFS patients.

Incollaboration with IanLipkin, MD, at ColumbiaUniversity, and utilizinginnovative technologiessuch as mass tag, PCR,Green chip, or 454 deepsequencing (which havenever been tried with CFSpatients), researchers mayfind known or unknownorganisms. Montoya alsocollaborates with otherStanford faculty and the Stanford Human Immune MonitoringCore Facility to analyze the blood through immunologicaltechniques. Several hundred patients are enrolled inthese studies.The Big PictureCFS is believed to affect between one and four millionAmericans and accounts for approximately $9 to $18 billionin lost productivity due to illness. Montoya’s long-term goalis to eliminate chronic fatigue syndrome. Slowly, he has introducedthe condition, which was previously ostracized byacademic centers into the division of infectious diseases. Hehopes that physicians who treat CFS patients will eventuallysee it as making a contribution to human health.“I think the future of infectious diseases is going to be inthe challenges posed by viruses, other intercellular pathogens,and chronic illnesses. For these we have poor diagnosticsand limited therapies. Connecting an unexplainedchronic illness and other diseases with these pathogenswill shape the future of our subspecialty. It will expand thetherapeutic armamentarium beyond treating extracellularbacteria and fungi to more challenging and unexplainedsyndromes associated with infection.”

Initial response by Professor Malcolm Hooper to an undated letter sent by Professor Peter White to Dr Richard Horton, Editor-in-Chief of The Lancet

18th May 2011

On 17th May 2011 Zoe Mullan, Senior Editor at The Lancet, sent an email to Professor Hooper in response to the complaint he submitted about the PACE Trial article published online by The Lancet on 18th February 2011 and subsequently in the journal on 5th March 2011. In her email, Zoe Mullan wrote: “We asked the authors of the PACE trial to respond to your concerns, which they have duly done. Your complaint and their response were discussed at the highest management level and this group of executive editors was fully satisfied that there were no grounds whatsoever on which to take further action. We attach the response provided to us here. From an editorial perspective, the case is now closed”.

The undated response to Professor Hooper’s complaint by Professors White, Sharpe and Chalder that was sent to Dr Richard Horton (Editor-in-Chief of The Lancet) on behalf of all the co-authors will, in the interests of openness and transparency, be placed in the public domain and will be fully addressed in due course, as will Professor Hooper’s concerns over what he believes is the failure of The Lancet’s editorial process in this instance, but there is one point in Professor White’s letter that is of particular importance, so it is addressed in this initial response.

In their letter, Peter White et al state: “The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME”.

The sentence continues by stating that the PACE Trial studied: “CFS defined simply as a principal complaint of fatigue that is disabling, having lasted six months, with no alternative medical explanation (Oxford criteria)”.

This is exactly what the ME/CFS community has been saying from the outset, namely that the PACE Trial was not studying those with ME.

Soon after the Oxford criteria were published in 1991, one of the co-authors, psychiatrist Anthony David, wrote in the British Medical Bulletin: “British investigators have put forward an alternative, less strict, operational definition which is essentially chronic…fatigue in the absence of neurological signs, (with) psychiatric symptoms…as common associated features” (AS David; BMB 1991:47:4:966-988).

Given that ME is a classified neurological disorder (ICD-10 G93.3), there thus ought to have been no dispute that the PACE Trial Investigators were not studying those with ME, but the Investigators have persistently confirmed that they were studying those with ME, for example:

2. The two versions of the PACE Trial Protocol (both the Full Protocol and short version that was published in BMC Neurology 2007:7:6) are equally clear; the PACE Trial was: “A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy”.

3. In the Glossary to the Full Protocol, Professor White et al specifically state that CFS/ME is the official term for the illness described in the “Working Group Report to the Chief Medical Officer (2002) and the MRC RAG Report (2003)”.

4. In the PACE Trial Patient Clinic Leaflet, Professor White et al state: “This illness is also known as post-viral fatigue syndrome, myalgic encephalomyelitis (ME) and myalgic encephalopathy (ME). Medical authorities are not certain that CFS is exactly the same illness as ME…but we will be calling this illness CFS/ME”.

In The Lancet article itself, Peter White et al use the term myalgic encephalomyelitis throughout the text and actually state: “Myalgic encephalomyelitis is thought by some researchers to be the same disorder….Several diagnostic criteria exist for chronic fatigue syndrome and myalgic encephalomyelitis”, thus implying that they had indeed studied those with ME.

Moreover, in the authors’ reply published in the Lancet on 17th May 2011 (The PACE trial in chronic fatigue syndrome – Authors’ reply), Peter White is unambiguous: “…however we defined CFS and myalgic encephalomyelitis, we found that cognitive behaviour therapy and graded exercise therapy provided a significant and clinically useful advantage….”.

Here, though, Professors White, Sharpe and Chalder have categorically stated that the PACE Trial “does not purport to be studying CFS/ME”.

This may explain why so many recruits were not accepted into the PACE Trial on the stated grounds they did not fulfil the Oxford criteria for “CFS” (which according to the Principal Investigators themselves, is not the same as “CFS/ME”).

If the PACE Trial was not studying CFS/ME (as now asserted by Professor White et al), then the results cannot be used by NICE to support its Clinical Guideline 53 for CFS/ME.

NICE, however, announced on 14th March 2011 that there will be no review of CG53 until 2013: “…interventions recommended in the original guideline, such as CBT and GET, were described as the interventions for which there is the clearest evidence-base of benefit. This is supported by the recently published PACE trial….The results of the study are in line with current NICE guideline recommendations on the management of CFS/ME….There are no factors…which would invalidate or change the direction of the current guideline recommendations. The CFS/ME guideline should not be updated at this time”.

Most certainly, this statement by the Principal Investigators that the PACE Trial did not purport to be studying those with CFS/ME raises important issues about the alleged generalisability of the PACE Trial results, given that The Lancet article unambiguously states: “The PACE findings can be generalised to patients who also meet alternative diagnostic criteria for chronic fatigue syndrome and myalgic encephalomyelitis but only if fatigue is their main symptom”.

That The Lancet supports the Principal Investigators’ inconsistent and indefensible position and refuses to engage with clearly articulated complaints must be of concern to anyone interested in the integrity of the scientific process.

Permission to repost.

My PS: Working group report to the Chief Medical Officer cfsmereport 2002: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4064840

"Plenty of people are still dying of diseases which other people do not believe." (Dr. M.N.C. Dukes).CBT and GET for ME: "There is no nonsense so gross that society will not, at some time, make a doctrine of it and defend it with every weapon of communal stupidity."

Robertson Davies

THE NICEGUIDELINES BLOG VERSUS THE NICEGUIDELINES

These are NOT the NICEGuidelines. This is "The NICEGUIDELINES BLOG." What are the differences:

The NICE Guidelines are biased publications based on the GOBSART (Good Old Boys Sitting Around a Table) approach.

This Blog however is not only evidence based but also uses critical reading to judge papers and articles. I also use common sense and listen to others. And finally I read both psychiatric and medical evidence and opinions from around the world to come to a conclusion.

I’m not sponsored by anybody or paid by whatever company as seems to be the norm with many psycho people who publish the same article almost on a weekly base.

So if you value an opinion, formed as a result of participating in many ME activities, for example being bed bound for years, you have come to the right BLOG. All these activities have allowed me to form an opinion as a Doctor and as a Patient. And that is important as the voice of the latter is discarded by many including NICE.

If you don’t read this blog, you will miss out on “accredited” medical education. If you do read it, you may actually become a doctor who doesn’t stop thinking or forgets to ask critical questions. Many good things, including satisfied patients are at your command.

So, if you arrived here for the straightforward GOBSART approach, I will disappoint you. If you are interested in forming your own opinion about ME, and other interesting things, read on!

About Dr. Speedy.

I am a Family Physician or GP as it is called in Australia or the UK. I am also an ME patient unfortunately. Bedbound that is. So at the moment I’m in private practice so to speak. I’ve got only one patient, ME, or is it me?

I graduated as a doctor a long time ago, and I am the founder and editor of The NICEGUIDELINES BLOG, an internet based ME BLOG that is devoted to critical reading and cheering you or ME up.

I have the following conflict of interest: I would like to get better and see that the wasting of public money on CBT (talk therapy for a neurological disease, really helpful) and other silly therapies for ME stops, and will be used in better ways.

My goal has always been to help, and if possible, cure patients. With this disease you will soon find out that many psychiatrists and psychologists are only in it to make money and get their name in the spotlight. And what happens to and with the patients is irrelevant.

I stand to benefit both mentally, physically and also financially if this silliness would stop, and I would get my health back, and I can go back to work and have a normal life again. Please evaluate my postings with this in mind! And remember, there are also (lots of) psychiatrists and psychologists who haven’t switched their brain off.